Childhood adversity is associated with increased risk for depression, posttraumatic disorder (PTSD), and disease vulnerability, a risk that continues into adulthood. This long-lasting impact of early adversity is attributed to the reprogramming or changes in the expression of genes regulating the hypothalamic-pituitary- adrenal (HPA) axis and immune responses, which impact biological and psychological processes. Activation of the HPA axis is an adaptive response to stress; however, when repeatedly activated over weeks or months, HPA axis dysregulation can result. Such dysregulation is associated with both depression and PTSD although a discrepant neuroendocrine profile is described. In depression, there are increased cortisol and reduced glucocorticoid receptor (GR) responsiveness whereas in PTSD, there are attenuated cortisol levels and enhanced GR responsiveness. It is possible that certain neuroendocrine profiles reflect a pre-existing vulnerability that puts individuals at isk for different outcomes in response to stress. Until recently, the assessment of HPA axis prior to stress would not have been possible. Hair cortisol analysis, a state of the art method, provides a retrospective measure of long-term HPA axis activity. Our aims are to recruit 40 children, 15-18 years of age, of parents diagnosed with stage IV lung cancer within two weeks of parental diagnosis and compare them to 20 control children whose parents/siblings do not have cancer or any chronic illnesses. The two groups will be followed 6 and 9 months after intake. At intake and 6 months, we propose to collect blood samples to quantify gene expression in the HPA axis and GR sensitivity. We measure hair cortisol concentrations (HCC) in the 2 cm segment of hair closest to the scalp, which reflects HPA axis activity over the past two months, and thus prior to parental diagnosis for the first assessment. We also collect salivary cortisol for short-term HPA axis activity. We measure clinical outcomes at intake and follow-ups. We hypothesize that children of parents with cancer will show increased GR expression and total salivary cortisol output in response to the acute stress of parental diagnosis at 2 weeks. At 6 months and in response to the chronic stress of parental diagnosis, there will be decreased GR expression and increased expression of inflammatory genes in children of parents with cancer. These will be associated with reduced GR sensitivity and increased HCC and salivary cortisol. HCC prior to stress will be negatively associated with prior trauma and will predict biological responses to acute and chronic stress, which will in turn predict depression and PTSD symptomatology, and other health outcomes. This R21 pilot study will gather feasibility data of the study design and will inform individual pathways of our proposed biological model that links chronic stress in childhood to increased risk of psychiatric illness and disease vulnerability through alterations in biological processes of gene expression and physiological responses. This R21 lays the foundation for a future project that will identify early biomarkers that signal risk for maladaptiv stress response and provide targets for new prevention and treatment approaches.